Dual modulation of cell survival and cell death by β ₂ -adrenergic signaling in adult mouse cardiac myocytes

The goal of this study was to determine whether β ₁ -adrenergic receptor (AR) and β ₂ -AR differ in regulating cardiomyocyte survival and apoptosis and, if so, to explore underlying mechanisms. One potential mechanism is that cardiac β ₂ -AR can activate both G _s and G _i proteins, whereas cardiac β ₁ -AR couples only to G _s . To avoid complicated crosstalk between β-AR subtypes, we expressed β ₁ -AR or β ₂ -AR individually in adult β ₁ /β ₂ -AR double knockout mouse cardiac myocytes by using adenoviral gene transfer. Stimulation of β ₁ -AR, but not β ₂ -AR, markedly induced myocyte apoptosis, as indicated by increased terminal deoxynucleotidyltransferase-mediated UTP end labeling or Hoechst staining positive cells and DNA fragmentation. In contrast, β ₂ -AR (but not β ₁ -AR) stimulation elevated the activity of Akt, a powerful survival signal; this effect was fully abolished by inhibiting G _i , G _{β γ} , or phosphoinositide 3 kinase (PI3K) with pertussis toxin, βARK-ct (a peptide inhibitor of G _{β γ} ), or LY294002, respectively. This indicates that β ₂ -AR activates Akt via a G _i -G _{β γ} -PI3K pathway. More importantly, inhibition of the G _i -G _{β γ} -PI3K-Akt pathway converts β ₂ -AR signaling from survival to apoptotic. Thus, stimulation of a single class of receptors, β ₂ -ARs, elicits concurrent apoptotic and survival signals in cardiac myocytes. The survival effect appears to predominate and is mediated by the G _i -G _{β γ} -PI3K-Akt signaling pathway.